Anti-herpesvirus activities and cytotoxicities of 2-thiopyrimidine nucleoside analogues in vitro

Twenty 2-thiopyrimidine nucleoside analogues were synthesized and examined for inhibitory activity against herpes simplex virus (HSV) type 1 and 2, va ricella-zoster virus (VZV), human cytomegalovirus (HCMV) and thymidine kina se-deficient HSV (HSV-TK-) replication in vitro. 2-thiouracil (thymine) ara binoside, 2'-deoxy-2-thiouridine (or 2-thiothymidine) and their 5-halogenat ed derivatives showed anti-HSV activity in both RPMI8226 (human B-lymphobla stoid cells) and MRC-5 (human embryo lung cells). 2'-deoxy-5-halogenated-2- thiocytidines were also inhibitory against HSV, whereas 2-thiocytosine arab inoside and its derivatives were not inhibitory against HSV replication, ex cept 5-bromo and 5-iodo congeners (TN-31. TN-32). Substitution of the halog en atom at the 5-position of the pyrimidine rings to an atom with a higher molecular weight increased anti-HSV and VZV activities, except for the anti -HSV activity of 2-thiouracil arabinosides. 2'-deoxy-5-methyl-, and 2'-deox y-5-iodo-2-thiouridines (TN-17. TN-44) showed the most potent anti-HSV acti vity, and 2'-deoxy-5-chloro- and 2'-deoxy-5-bromo-2-thiocytidines were pote nt inhibitors of VZV replication. However, none of the compounds inhibited HCMV and HSV-TK- replication. TN-31 and TN-32 were shown to inhibited HCMV and HSV-TK- as well as HSV and VZV replication. The cytotoxicity of the 2-t hio-pyrimidine nucleoside analogues was less than that of the 2-oxy-congene rs of the compounds (5-iodo-2'-deoxyuridine, 5-iodo-2'-deoxycytidine, thymi ne arabinoside and cytosine arabinoside). The selectivity index of 2'-deoxy -5-iodo-thiouridine (TN-44) was higher than that of 5-iodo-deoxyuridine TN- 17 and TN-44 were not cytotoxic to resting or stimulated human peripheral b lood mononuclear cells at 400 mu M, although TN-32 was cytotoxic at a conce ntration of 20 mu M.